EP1789410A1 - Methylene dipiperidine derivatives - Google Patents
Methylene dipiperidine derivativesInfo
- Publication number
- EP1789410A1 EP1789410A1 EP05789636A EP05789636A EP1789410A1 EP 1789410 A1 EP1789410 A1 EP 1789410A1 EP 05789636 A EP05789636 A EP 05789636A EP 05789636 A EP05789636 A EP 05789636A EP 1789410 A1 EP1789410 A1 EP 1789410A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- heteroaryl
- aryl
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to novel methylene dipiperidine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.
- WO 2002/43762 and WO 00/59510 both describe a series of heterocyclyl substituted pyrimidine derivatives which are claimed to be useful in the treatment of diabetes.
- JO 4018-071 -A (Sumitomo Seiyaku KK) describes a series of bis-piperidine derivatives which are claimed to be acetylcholine esterase inhibitors for the treatment of Alzheimer's disease.
- the histamine H3 receptor is predominantly expressed in the mammalian central nervous system (CNS), with minimal expression in peripheral tissues except on some sympathetic nerves (Leurs et al., (1998), Trends Pharmacol. Sci. 19, 177-183). Activation of H3 receptors by selective agonists or histamine results in the inhibition of neurotransmitter release from a variety of different nerve populations, including histaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam. Clin. Pharmacol. 8, 128-137).
- H3 antagonists can facilitate neurotransmitter release in brain areas such as the cerebral cortex and hippocampus, relevant to cognition (Onodera et al., (1998), In: The Histamine H3 receptor, ed Leurs and Timmerman, pp255- 267, Elsevier Science B.V.).
- H3 antagonists e.g. thioperamide, clobenpropit, ciproxifan and GT-2331
- rodent models including the five choice task, object recognition, elevated plus maze, acquisition of novel task and passive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104, 147-155).
- the present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
- R 1 represents aryl, heteroaryl,-aryl-X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, - heteroaryl-X-heteroaryl, -heteroaryl-X-aryl or -heteroaryl-X-heterocyclyl; wherein said aryl, heteroaryl and heterocyclyl groups of R 1 may be optionally substituted by one or more (e.g.
- substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC 1-6 alkyl, polyhaloCi-6 alkyl, haloC 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyloxy, C 1-6 alkylsulfonylC 1-6 alkyl, C 1-6 alkylsulfonamidoCi -6 alkyl, C 1-6 alkylamidoC 1-6 alkyl, phenyl, phenylsulfonyl, phenylsulfonamido
- X represents a bond, O, CO, SO 2 , OCH 2 or CH 2 O;
- R 2 represents C 1-8 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl or -C 1- 4 alkyl-C 3-6 cycloalkyl; wherein said C 3-6 cycloalkyl groups of R 2 may be optionally substituted by one or more (e.g. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, C 1-4 alkyl or polyhaloCi -6 alkyl groups; each R 3 and R 4 group independently represents C 1-4 alkyl; m and n independently represents 0, 1 or 2; or solvates thereof.
- the invention provides compounds of formula (I) wherein:
- R 1 represents aryl, heteroaryl, -aryl-X-aryl, -aryl-X-heteroaryl, -aryl-X-heterocyclyl, - heteroaryl-X-heteroaryl, -heteroaryl-X-aryl or -heteroaryl-X-heterocyclyl; wherein said aryl, heteroaryl and heterocyclyl groups of R 1 may be optionally substituted by one or more (e.g.
- substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, haloC 1-6 alkyl, polyhaloC 1-6 alkyl, halod-e alkoxy, polyhaloC 1-6 alkoxy, Ci -6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyloxy, C 1-6 alkylsulfonylC 1-6 alkyl, C 1-6 alkylsulfonamidoC ⁇ alkyl, C 1-6 alkylamidoC 1-6 alkyl, aryl,
- R 2 represents C 3-8 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl or -C 1- 4 alkyl-C 3-6 cycloalkyl; wherein said C 3-6 cycloalkyl groups of R 2 may be optionally substituted by one or more (e.g. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, C 1-4 alkyl or polyhaloC ⁇ alkyl groups; each R 3 and R 4 group independently represents C 1-4 alkyl; m and n independently represents O, 1 or 2; or a pharmaceutically acceptable salt thereof.
- R 1 represents -heteroaryl, -heteroaryl-X-aryl, -heteroaryl-X- heteroaryl or -heteroaryl-X-heterocyclyl
- the heteroaryl group attached directly to the piperidine is other than benzoxazol-2-yl.
- R 1 is other than pyrimidin-4-yl.
- R 1 represents -heteroaryl
- R 2 does not represent - methyl-C 3-6 cycloalkyl
- 'C 1-6 alkyl' refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
- examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
- 'C 2-6 alkenyl' refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds and having from 2 to 6 carbon atoms.
- Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
- 'C 1-6 alkoxy' refers to an -0-C 1-6 alkyl group wherein C 1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
- 'C 3-8 cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
- 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
- 'haloC 1-6 alkyl' refers to a C 1-6 alkyl group as defined herein wherein one hydrogen atom is replaced with halogen.
- An example of such a group includes fluoroethyl.
- 'polyhaloC 1-6 alkyl' as used herein refers to a C 1-6 alkyl group as defined herein wherein at least two hydrogen atoms are replaced with halogen. Examples such groups include trifluoromethyl or trifluoroethyl and the like.
- 'halo C 1-6 alkoxy' refers to a C 1-6 alkoxy group as herein defined wherein one hydrogen atom is replaced with halogen.
- An examples of such a group includes fluoromethoxy.
- 'polyhaloC 1-6 alkoxy' as used herein refers to a C 1-6 alkoxy group as defined herein wherein at least two hydrogen atoms are replaced with halogen. Examples such groups include difluoromethoxy or trifluoromethoxy and the like.
- 'C 1-6 alkylamidoC 1-6 alkyl' as used herein encompasses the group -C 1-6 alkyl- CONH-C 1-6 alkyl, and the group -C 1-6 alkyl-NHCO-C 1-6 alkyl.
- 'aryl' refers to a C 6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or tetrahydronaphthalenyl and the like.
- 'aryloxy' refers to an -O-aryl group wherein aryl is as defined herein. Examples of such groups include phenoxy and the like.
- heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
- Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
- fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
- heterocyclyl refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur.
- Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and the like.
- bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine, tetrahydroisoquinolinyl and the like.
- R 1 represents -aryl, -heteroaryl, -aryl-X-heteroaryl or heteroaryl-X- heteroaryl.
- R 1 represents -aryl-X-heteroaryl or -heteroaryl-X-heteroaryl and the aryl or heteroaryl linked to the nitrogen atom of the piperidine group is a 6 membered ring
- the bond to X is in the para position relative to the attachment to the linkage to the nitrogen atom of the piperidine group.
- the aryl or heteroaryl groups of R 1 may optionally be substituted by one or more (e.g. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, cyano, Ci -6 alkyl, polyhaloC 1-6 alkyl, or a group -COR 15 , -COOR 15 Or -CONR 15 R 16 , wherein R 15 and R 16 independently represent, hydrogen, C 1-6 alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl) or polyhaloC 1-6 alkyl (e.g. trifluoromethyl).
- substituents which may be the same or different, and which are selected from the group consisting of halogen, cyano, Ci -6 alkyl, polyhaloC 1-6 alkyl, or a group -COR 15 , -COOR 15 Or -CONR 15 R 16 , wherein R 15 and R 16
- R 1 represents -aryl or -heteroaryl, wherein the aryl and heteroaryl groups are six membered rings that are substituted by one substitutent, the substituent is in the para position relative to the attachment to X.
- R 1 represents:
- -aryl e.g. phenyl
- a -COR 15 e.g. -COMe or -COCF 3
- halogen e.g. fluorine
- -heteroaryl e.g. pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-5-yl or quinolin-6-yl
- a cyano C 1-6 alkyl (e.g. methyl), polyhaloC 1-6 alkyl (e.g. -CF 3 ), -CONR 15 R 16 (e.g. -CON(H)(Me), -CON(H)(Et), -C0N(H)(i-
- -COR 15 e.g. -COMe
- -COOR 15 e.g. -COOt-Bu
- -aryl-X-heteroaryl e.g.-phenyl-oxadiazolyl
- a halogen e.g. fluorine
- Ci -6 alkyl e.g. methyl
- -heteroaryl-X-heteroaryl e.g. -pyridyl-oxadiazolyl
- C 1-6 alkyl e.g. methyl
- R 1 represents:
- -aryl e.g. phenyl
- a -COR 15 e.g. -COMe or -COCF 3
- -heteroaryl e.g. pyrid-2-yl, pyrid-3-yl, pyrazin-2-yl, pyridazin-3-yl or pyrimidin-5-yl
- a cyano, polyhaloCi -6 alkyl e.g. -CF 3
- -CONR 15 R 16 e.g. - CON(H)(Me), -CON(H)(Et), -CON(H)(J-Pr) 1 -COR 15 (e.g. -COMe) or -COOR 15 (e.g. - COOH, -COOMe or -COOt-Bu) group
- a cyano e.g. pyrid-2-yl, pyrid-3-yl, pyrazin-2-y
- -aryl-X-heteroaryl e.g.-phenyl-1 ,2,4-oxadiazol-5-yl
- the aryl group is optionally substituted by a halogen (e.g. fluorine)
- the heteroaryl group is optionally substituted by C 1-6 alkyl (e.g. methyl);
- -heteroaryl-X-heteroaryl e.g. -pyrid-3-yl-1 ,2,4-oxadiazol-5-yl
- a C 1-6 alkyl e.g. methyl
- R 1 represents -heteroaryl (e.g. pyrid-3-yl or pyrazin-2-yl) optionally substituted by a cyano, -
- CONR 15 R 16 e.g. -CON(H)(Me), -CON(H)(Et) or -CON(H)(J-Pr)
- -COR 15 e.g. -COMe
- -aryl-X-heteroaryl e.g. -phenyl-1 ,2,4-oxadiazol-5-yl
- a halogen e.g. fluorine
- a C 1-6 alkyl e.g. methyl
- -heteroaryl-X-heteroaryl e.g. -pyrid-3-yl-1 ,2,4-oxadiazol-5-yl
- a C 1-6 alkyl e.g. methyl
- R 1 represents -pyrazin-2-yl or pyrid-3-yl optionally substituted by -CONR 15 R 16 (e.g. -CON(H)(Me),
- -phenyl-1 ,2,4-oxadiazol-5-yl optionally substituted on the phenyl group by a halogen (e.g. fluorine) and optionally substituted on the oxadiazolyl group by a C 1-6 alkyl (e.g. methyl) group.
- a halogen e.g. fluorine
- a C 1-6 alkyl e.g. methyl
- X represents a bond
- R 2 represents C 1-8 alkyl (e.g. methyl, ethyl or isopropyl), C 3-6 cycloalkyl (e.g. cyclobutyl), C 1-4 alkyl-C 3- ecycloalkyl (e.g. cyclopropylmethyl).
- R 2 represents isopropyl or cyclobutyl, particularly cyclobutyl.
- m and n both represent O.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents aryl, heteroaryl, -aryl-X-heteroaryl, or -heteroaryl-X-heteroaryl; wherein said aryl, heteroaryl and heterocyclyl groups of R 1 may optionally be substituted by one or more (e.g. 1 , 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, cyano, Ci -6 alkyl, polyhaloC 1-6 alkyl, or a group -COR 15 , -COOR 15 or -CONR 15 R 16 ; X represents a bond;
- R 2 represents C 1-8 alkyl, C 3-6 cycloalkyl or -Ci- 4 alkyl-C 3-6 cycloalkyl; m and n represent O; or solvates thereof.
- Compounds according to the invention include examples E1-E36 as shown below, or a pharmaceutically acceptable salt or solvate thereof.
- compounds according to the invention include:
- compounds according to the invention include:
- a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
- a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic
- a pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt.
- a hydrobromide hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-to
- the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) including hydrates and solvates.
- Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.
- the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
- R 2 , R 3 , R 4 , m and n are as defined above, with a compound of formula R 1 -l_ ⁇ wherein R 1 is as defined above and L 1 represents a suitable leaving group, such as a halogen atom (e.g. fluorine, chlorine, bromine or iodine); or
- Process (a) typically comprises the use of a suitable base, such as potassium carbonate in a suitable solvent such as dimethylsulfoxide, 1-methyl-2-pyrrolidinone, N 1 N- dimethylformamide or acetonitrile at elevated temperature.
- a suitable base such as potassium carbonate
- a suitable solvent such as dimethylsulfoxide, 1-methyl-2-pyrrolidinone, N 1 N- dimethylformamide or acetonitrile
- process (a) may be carried out with a suitable catalyst system in the presence of a suitable base such as sodium t-butoxide, caesium carbonate or potassium phosphate in a solvent such as o- xylene, dioxane or toluene, under an inert atmosphere, optionally at an elevated temperature.
- Suitable catalyst systems include tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, bis(dibenzylideneacetone)palladium and 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl, tris(dibenzylideneacetone)dipalladium(0) and xantphos, acetato(2'-di-t-butylphosphino-1 ,1 '-biphenyl-2-yl)palladium (II), palladium(ll) acetate and BINAP, or palladium(ll) acetate and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane.
- Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2 ⁇ 2',2'- trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
- Suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
- Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
- interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
- transition metal mediated coupling reactions useful as interconversion procedures include the following:
- Palladium catalysed coupling reactions between organic electrophiles such as aryl halides, and organometallic reagents, for example boronic acids (Suzuki cross-coupling reactions); Palladium catalysed amination and amidation reactions between organic electrophiles, such as aryl halides, and nucleophiles, such as amines and amides; Copper catalysed amidation reactions between organic electrophiles (such as aryl halides) and nucleophiles such as amides; and Copper mediated coupling reactions between phenols and boronic acids.
- organic electrophiles such as aryl halides
- organometallic reagents for example boronic acids (Suzuki cross-coupling reactions)
- Palladium catalysed amination and amidation reactions between organic electrophiles such as aryl halides, and nucleophiles, such as amines and amides
- L 2 represents a suitable leaving group such as a halogen atom (e.g. bromine), and P 1 represents a suitable protecting group such as t-butoxycarbonyl.
- Step (i) comprises the use of a borane such as 9-borabicyclo[3.3.1]nonane in a solvent such as tetrahydrofuran, followed by treatment with a suitable palladium catalyst such as [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1 :1), in the presence of a base such as potassium carbonate in a suitable solvent such as N,N-dimethylformamide, at elevated temperature.
- a borane such as 9-borabicyclo[3.3.1]nonane in a solvent such as tetrahydrofuran
- a suitable palladium catalyst such as [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1 :1)
- a base such as potassium carbonate
- a suitable solvent such as N,N-dimethylformamide
- Step (ii) is carried out under reductive conditions using hydrogen gas with a platinum catalyst in a solvent such as ethanol at a suitable temperature such as room temperature.
- Step (iii) may be performed by reacting a compound of formula (Vl) with a compound of formula R 2 -L 3 wherein R 2 is as defined above and L 3 represents a suitable leaving group such as a halogen atom or a sulfonate.
- L 3 represents halogen (e.g. iodine) or a sulfonate (e.g. methylsulfonate)
- step (iii) typically comprises the use of a suitable base such as potassium carbonate in a solvent such as acetonitrile optionally at elevated temperature.
- Step (iii) typically takes place, under reductive conditions e.g. using sodium triacetoxyborohydride and a suitable base such as triethylamine, in a solvent such as DCM.
- Step (iv) is a deprotection reaction where the conditions depend on the nature of the group P 1 .
- Process (b) describes processes for removing protecting groups. Removal of a P 1 tert- butoxycarbonyl group can be performed under acidic conditions e.g. using 4N HCI in a suitable solvent such as dioxane.
- Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are antagonists and/or inverse agonists of the histamine H3 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain and back pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders (including narcolepsy and sleep deficits associated with Parkinson's disease); psychiatric disorders including schizophrenia (particularly cognitive deficit of schizophrenia), attention deficit hypereactivity disorder, depression, anxiety and addiction; and other diseases including obesity and gastro ⁇ intestinal disorders.
- neurological diseases including Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, cognitive deficit, epilepsy, pain of
- compounds of formula (I) are expected to be selective for the histamine H3 receptor over other histamine receptor subtypes, such as the histamine H1 receptor.
- compounds of the invention may be at least 10 fold selective for H3 over H1 , such as at least 100 fold selective.
- the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders, in particular cognitive impairments in diseases such as Alzheimer's disease and related neurodegenerative disorders.
- the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
- the compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
- the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the present invention further provides a pharmaceutical composition which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
- Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT 6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonists or acetylcholinesterase inhibitors.
- the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
- the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
- compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
- the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
- a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
- Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
- fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
- the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
- suitable unit doses may be 0.05 to 1000 mg, more suitably 0.1 to 200 mg and even more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
- 9-borabicyclo[3.3.1]nonane 101.5ml of a 0.5M solution in tetrahydrofuran was added to a degassed sample of ⁇ /-(tert-butoxycarbonyl)-4-methylene piperidine (may be prepared as described in A. Palani et al., J. Med. Chem., 2002, 45: 3145) (10g) and the resultant solution heated at reflux for 1h.
- This material and ⁇ /, ⁇ /-dimethylacetamide dimethylacetal were heated together at 120 0 C for 2h.
- the reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate.
- the organic extract was washed with water and brine, dried and evaporated to give the acylamidine intermediate as a gum which solidified in vacuo, overnight (12.3 g).
- This intermediate was treated with a solution of hydroxylamine hydrochloride (4.16g) in 1 M aqueous sodium hydroxide (74.2ml), dioxane (75ml) and glacial acetic acid (95ml).
- 1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.5Og), methyl 5-chloro-2-pyrazinecarboxylate (0.575g) and potassium carbonate (0.615g) were dissolved in acetonitrile (5ml) and heated at 120 0 C for 5min in the microwave reactor. The crude mixture was passed through an SCX column (10g, eluting with methanol [80ml] then 2N NH 3 in methanol [8OmI]). The basic fractions were evaporated to give the title compound (E2) as a yellow crystalline solid (0.825g). MS electrospray (+ion)
- 1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine may be prepared as described in Description 6) (0.5Og), 1 ,1-dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.66g), BINAP (0.15g) and Cs 2 CO 3 (1.6g) were added to toluene (20ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3 ⁇ ). After stirring for 5 min Pd(OAc) 2 (0.05g) was added and the reaction mixture heated at 80 0 C for 2Oh.
- 1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.25g), 1,1 -dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.29g), BINAP (0.06g) and Cs 2 CO 3 (1.82g) were added to toluene (50ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3 ⁇ ). After stirring for 5 min Pd(OAc) 2 (0.05g) was added, degassed again, and the reaction mixture heated at 100 0 C for 24h.
- Step 1 5- ⁇ 4-[(1-cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl ⁇ -2-pyrazinecarbonyl chloride
- Step 2 5- ⁇ 4-[(1-Cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl ⁇ - ⁇ /-(1-methylethyl)-2- pyrazinecarboxamide
- Examples 7-9 were prepared using an analogous process to that described in Examples 5 and 6 from either methyl 5- ⁇ 4-[(1-cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl ⁇ -2- pyrazinecarboxylate (may be prepared as described in Example 1 ) or methyl 5-(4- ⁇ [1-(1- methylethyl)-4-piperidinyl]methyl ⁇ -1-piperidinyl)-2-pyrazinecarboxylate (may be prepared as described in Example 2) and the amine indicated in the table below. All compounds displayed 1 H-NMR and mass spectral data that were consistent with structure.
- Step 1 5- ⁇ 4-[(1 -Cyclobutyl-4-piperidinyl)methyl]-1 -piperidinyl ⁇ -2-pyridinecarbonyl chloride hydrochloride 5- ⁇ 4-[(1-Cyclobutyl-4-piperidinyl)methyl]-1-piperidinyl ⁇ -2-pyridinecarboxylic acid tris trifluoroacetate (may be prepared as described in Example 10) (0.264g) was dissolved in DCM (20ml) with oxalyl chloride (0.2ml) and dimethylformamide (1 drop). After 3h the reaction mixture was evaporated and the resultant yellow foam re-evaporated from dichloromethane (3 ⁇ 20ml) to give the crude acid chloride, which was used in the next step immediately.
- Step 2 5- ⁇ 4-[(1 -Cyclobutyl-4-piperidinyl)methyl]-1 -piperidinyl ⁇ - ⁇ /-methyl-2- pyridinecarboxamide
- Examples 16-20 (E16-E20) Examples 16 to 20 were prepared using an analogous process to that described in
- Example 22 was prepared using an analogous process to that described in Example 21 from 1-cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) and ⁇ -bromo ⁇ -pyridinecarbonitrile.
- the compound displayed 1 H-NMR and mass spectral data that were consistent with structure. MS electrospray (+ion) 339 (MH + ).
- Example 24 was prepared using an analogous process to that described in Example 23 from S ⁇ - ⁇ i-Cyclobutyl ⁇ -piperidinyOmethyll-i-piperidinylJ ⁇ -pyridinecarbonitrile (may be prepared as described in Example 22). 1 H-NMR and mass spectral data were consistent with structure. MS electrospray (+ion) 356 (MH + ).
- Examples 26-32 were prepared using an analogous process to that described in Example 25 from either 1-cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6), 1-(1-methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4), 1 -ethyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 8), 1-(cyclopropylmethyl)-4-(4- piperidinylmethyl)piperidine (may be prepared as described in Description 10) or 1-methyl- 4-(4-piperidinylmethyl)piperidine (D19), and either 4-fluoroacetophenone, 2,2,2,4'- tetrafluoroacetophenone or 1-(6-chloro-3-pyridinyl)-1-ethanone.
- Compounds displayed 1 H- NMR and mass spectral data that were consistent with structure.
- Examples 33-34 were prepared using an analogous process to that described in Example 25 from either 1-cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) or 1-(1-methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) and 3-chloro-6-trifluoromethylpyridazine (may be prepared as described in Goodman, Allan J.; Stanforth, Stephen P.; Tarbit, Brian. Tetrahedron (1999), 55(52), 15067-15070).
- Compounds displayed 1 H-NMR and mass spectral data that were consistent with structure.
- 1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine may be prepared as described in Description 6) (0.15g), 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327) (0.129g), tris(dibenzylidineacetone)dipalladium(0) (0.053g), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl (0.088g) and sodium terf-butoxide (0.092g) were added to dioxane (2ml) and heated at 120 0 C for 14min in the microwave reactor.
- Example 36 was prepared using an analogous process to that described in Example 35 from 1-(1-methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) and 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327).
- 1 H-NMR and mass spectral data were consistent with structure. MS electrospray (+ion) 371 (MH + ).
- a membrane preparation containing histamine H3 receptors may be prepared in accordance with the following procedures:
- coli host bacterial cells and plated onto Luria Broth (LB) agar containing ZeocinTM (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 ⁇ g ml "1 .
- Colonies containing the re-ligated plasmid were identified by restriction analysis.
- DNA for transfection into mammalian cells was prepared from 250ml cultures of the host bacterium containing the pGeneH3 plasmid and isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).
- CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) were seeded at 2x10e6 cells per T75 flask in Complete Medium, containing Hams F12
- Plasmid DNA was transfected into the cells using Lipofectamine plus according to the manufacturers guidelines (InVitrogen). 48 hours post transfection cells were placed into complete medium supplemented with 500 ⁇ g ml "1 ZeocinTM.
- Positively stained cells were sorted as single cells into 96-well plates, containing Complete Medium containing 500 ⁇ g ml "1 ZeocinTM and allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies.
- the cell pellet is resuspended in 10 volumes of homogenisation buffer (5OmM N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 1mM ethylenediamine tetra- acetic acid (EDTA), pH 7.4 with KOH, supplemented with 10e-6M leupeptin (acetyl-leucyl- leucyl-arginal; Sigma L2884), 25 ⁇ g/ml bacitracin (Sigma B0125), , 1 mM phenylmethylsulfonyl fluoride (PMSF) and 2x10e-6M pepstain A (Sigma)).
- HEPES homogenisation buffer
- EDTA 1mM ethylenediamine tetra- acetic acid
- pH 7.4 with KOH pH 7.4 with KOH
- 10e-6M leupeptin acetyl-leucyl- leucyl-arginal; Sigma
- the cells are then homogenised by 2 x 15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 50Og for 20 minutes. The supernatant is then spun at 48,00Og for 30 minutes. The pellet is resuspended in homogenisation buffer (4X the volume of the original cell pellet) by vortexing for 5 seconds, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at -80 0 C.
- the human H1 receptor was cloned using known procedures described in the literature [Biochem. Biophys. Res. Commun. 1994, 201(2), 894]. Chinese hamster ovary cells stably expressing the human H1 receptor were generated according to known procedures described in the literature [Br. J. Pharmacol. 1996, 117(6), 1071].
- test compound for each compound being assayed, in a solid white 384 well plate, is added:- (a) 5 ⁇ l of test compound diluted to the required concentration in 10% DMSO (or 5 ⁇ l 10% DMSO as a control); and
- the plate is centrifuged for 5 min at 1500 rpm and counted on a Viewlux counter using a 613/55 filter for 5 min/plate. Data is analysed using a 4-parameter logistical equation. Basal activity used as minimum i.e. histamine not added to well.
- Histamine H1 functional antagonist assay The histamine H1 cell line was seeded into non-coated black-walled clear bottom 384-well tissue culture plates in alpha minimum essential medium (Gibco /Invitrogen, cat no. 22561- 021), supplemented with 10% dialysed foetal calf serum (Gibco/lnvitrogen cat no. 12480- 021 ) and 2 mM L-glutamine (Gibco/lnvitrogen cat no 25030-024) and maintained overnight at 5% CO 2 , 37°C.
- alpha minimum essential medium Gibco /Invitrogen, cat no. 22561- 021
- dialysed foetal calf serum Gibco/lnvitrogen cat no. 12480- 021
- 2 mM L-glutamine Gibco/lnvitrogen cat no 25030-024
- Functional antagonism is indicated by a suppression of histamine induced increase in fluorescence, as measured by the FLIPRTM system (Molecular Devices). By means of concentration effect curves, functional affinities are determined using standard pharmacological mathematical analysis.
- Examples E6-E7 and E12-E13 were tested in the histamine H3 functional antagonist assay (method A). The results are expressed as functional pK, (fpK,) values.
- a functional pKi is the negative logarithm of the antagonist equilibrium dissociation constant as determined in the H3 functional antagonist assay using membrane prepared from cultured H3 cells. The results given are averages of a number of experiments. These compounds exhibited antagonism > 8 fpK,. More particularly the compounds of Example E6 and E12-13 exhibited antagonism ⁇ 9.0 fpK,. Even more particularly, the compound of Example E13 exhibited antagonism ⁇ 9.5 fpK,.
- Examples E8-E9, E11-E12 and E14-36 were tested in the histamine H3 functional antagonist assay (method B). Again, the results are expressed as functional pK, (fpK,) values and are averages of a number of experiments. These compounds exhibited antagonism ⁇ 8 fpK,. More particularly the compounds of Examples E8-E9, E11-12, E14- 18, E21-27, E29, E31 and E34 exhibited antagonism ⁇ 9.0 fpK,. Even more particularly, the compounds of Examples E16, E18, E22 and E24 exhibited antagonism ⁇ 9.5 fpK,.
- the compounds of Examples E6-E9 and E11-E36 were tested in the histamine H1 functional antagonist assay.
- the results are expressed as functional pK, (fpK,) values and are averages of a number of experiments.
- the functional pKi may be derived from the negative logarithm of the plC50 (concentration producing 50% inhibition) in the H1 functional antagonist assay according to the Cheng-Prusoff equation (Cheng, Y.C. and Prusoff, W. H., 1973, Biochem. Pharmacol. 22, 3099-3108.). All compounds tested exhibited antagonism ⁇ 6.0 fpKj.
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GB0420831A GB0420831D0 (en) | 2004-09-17 | 2004-09-17 | Novel compounds |
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US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
UA98772C2 (en) | 2006-06-23 | 2012-06-25 | Эбботт Леборетриз | Cyclopropyl amine derivatives as histamin h3 receptor modulators |
EP2155689B1 (en) * | 2007-05-31 | 2015-07-08 | Boehringer Ingelheim International GmbH | Ccr2 receptor antagonists and uses thereof |
EA020548B1 (en) | 2008-12-19 | 2014-12-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd |
US9186353B2 (en) * | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
WO2011029633A1 (en) * | 2009-09-14 | 2011-03-17 | Recordati Ireland Limited | Heterocyclic mglu5 antagonists |
ES2524829T3 (en) | 2009-12-17 | 2014-12-12 | Boehringer Ingelheim International Gmbh | New CCR2 receptor antagonists and uses thereof |
CA2788721A1 (en) * | 2010-02-04 | 2011-08-11 | Timothy J. Laros | Method for treating tailings |
EP2569298B1 (en) | 2010-05-12 | 2015-11-25 | Boehringer Ingelheim International GmbH | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
US8946218B2 (en) | 2010-05-12 | 2015-02-03 | Boehringer Ingelheim International Gmbh | CCR2 receptor antagonists, method for producing the same, and use thereof as medicaments |
JP5647339B2 (en) | 2010-05-17 | 2014-12-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | CCR2 antagonists and uses thereof |
US9018212B2 (en) | 2010-05-25 | 2015-04-28 | Boehringer Ingelheim International Gmbh | Pyridazine carboxamides as CCR2 receptor antagonists |
EP2576538B1 (en) | 2010-06-01 | 2015-10-28 | Boehringer Ingelheim International GmbH | New CCR2 antagonists |
WO2012037258A1 (en) | 2010-09-16 | 2012-03-22 | Abbott Laboratories | Processes for preparing 1,2-substituted cyclopropyl derivatives |
WO2013010839A1 (en) | 2011-07-15 | 2013-01-24 | Boehringer Ingelheim International Gmbh | Novel and selective ccr2 antagonists |
WO2013151982A1 (en) | 2012-04-03 | 2013-10-10 | Arena Pharmaceuticals, Inc. | Methods and compounds useful in treating pruritus, and methods for identifying such compounds |
EP2647377A1 (en) | 2012-04-06 | 2013-10-09 | Sanofi | Use of an h3 receptor antagonist for the treatment of alzheimer's disease |
JP6917910B2 (en) | 2015-07-02 | 2021-08-11 | セントレクシオン セラピューティクス コーポレイション | (4-((3R, 4R) -3-methoxytetrahydro-pyran-4-ylamino) piperidine-1-yl) (5-methyl-6-(((2R, 6S) -6- (P-tolyl) tetrahydro) -2H-pyran-2-yl) methylamino) pyrimidine-4yl) metanone citrate |
EP3383853B1 (en) * | 2015-12-01 | 2020-11-04 | Merck Sharp & Dohme Corp. | Homobispiperidinyl derivatives as liver x receptor (lxr) beta agonists for treating e.g. alzheimer's disease |
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UA59433C2 (en) | 1998-01-27 | 2003-09-15 | Авентіс Фармасьютікалс Продактс Інк. | Substituted oxoazaheterocyclyl inhibitors of xa factor |
AP2005003199A0 (en) | 1999-04-01 | 2005-03-31 | Pfizer Prod Inc | Aminopyrimidines as sorbitol dehydrogenase inhibitors |
BR0013179A (en) | 1999-07-28 | 2002-04-02 | Aventis Pharm Prod Inc | Substituted oxoazaeterocyclyl compounds |
PE20020507A1 (en) | 2000-10-17 | 2002-06-25 | Schering Corp | NON-IMIDAZOLE COMPOUNDS AS ANTAGONISTS OF THE HISTAMINE H3 RECEPTOR |
AU2002215159A1 (en) | 2000-11-30 | 2002-06-11 | Pfizer Products Inc. | Combination of GABA agonists and sorbitol dehydrogenase inhibitors |
AU2002253929A1 (en) | 2001-02-08 | 2002-09-24 | Schering Corporation | Use of dual h3/m2 antagonists with a bipiperidinic structure in the treatment of cognition deficit disorders |
US6660858B2 (en) | 2001-03-28 | 2003-12-09 | Lion Bioscience Ag | 2-aminobenzoxazole derivatives and combinatorial libraries thereof |
US6956040B2 (en) * | 2001-07-16 | 2005-10-18 | Ranbaxy Laboratories Limited | Oxazolidinone piperazinyl derivatives as potential antimicrobials |
JP4563675B2 (en) * | 2001-10-12 | 2010-10-13 | ハイ・ポイント・ファーマスーティカルズ、エルエルシー | Substituted piperidines and their use for the treatment of histamine H3 receptor related diseases |
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